Adrian M Di Bisceglie1, Ewa Janczweska-Kazek2, François Habersetzer3, Wlodzimierz Mazur4, Carol Stanciu5, Vicente Carreno6, Coman Tanasescu7, Robert Flisiak8, Manuel Romero-Gomez9, Alexander Fich10, Vincent Bataille11, Myew-Ling Toh11, Marie Hennequi11, Patricia Zerr11, Géraldine Honnet11, Geneviève Inchauspé11, Delphine Agathon11, Jean-Marc Limacher11, Heiner Wedemeyer12. 1. Department of Internal Medicine, St. Louis University Liver Center, St. Louis, Missouri. 2. Department of Infectious Diseases, Medical University of Silesia, Chorzow, Poland. 3. Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France. 4. Department of Internal Medicine, Medical University of Silesia, Katowice, Poland. 5. Institute of Gastroenterology and Hepatology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania. 6. Foundation for the Study of Viral Hepatitis, Madrid, Spain. 7. Internal Medicine Clinic, Colentina Clinical Hospital, Bucharest, Romania. 8. Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland. 9. Unit for the Clinical Management of Digestive Diseases and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Valme University Hospital, Sevilla, Spain. 10. Department of Gastroenterology, Soroka Medical Center, Beersheba, Israel. 11. Transgene, Illkirch, France. 12. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: wedemeyer.heiner@mh-hannover.de.
Abstract
BACKGROUND & AIMS:TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection. METHODS:Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. RESULTS: In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B (P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. CONCLUSIONS: A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.
RCT Entities:
BACKGROUND & AIMS:TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection. METHODS: Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. RESULTS: In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B (P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. CONCLUSIONS: A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.
Authors: Christabel Kelly; Leo Swadling; Stefania Capone; Anthony Brown; Rachel Richardson; John Halliday; Annette von Delft; Ye Oo; David Mutimer; Ayako Kurioka; Felicity Hartnell; Jane Collier; Virginia Ammendola; Mariarosaria Del Sorbo; Fabiana Grazioli; Maria Luisa Esposito; Stefania Di Marco; Loredana Siani; Cinzia Traboni; Adrian V S Hill; Stefano Colloca; Alfredo Nicosia; Riccardo Cortese; Antonella Folgori; Paul Klenerman; Eleanor Barnes Journal: Hepatology Date: 2016-01-22 Impact factor: 17.425
Authors: Leo Swadling; John Halliday; Christabel Kelly; Anthony Brown; Stefania Capone; M Azim Ansari; David Bonsall; Rachel Richardson; Felicity Hartnell; Jane Collier; Virginia Ammendola; Mariarosaria Del Sorbo; Annette Von Delft; Cinzia Traboni; Adrian V S Hill; Stefano Colloca; Alfredo Nicosia; Riccardo Cortese; Paul Klenerman; Antonella Folgori; Eleanor Barnes Journal: Vaccines (Basel) Date: 2016-08-02